Gene Summary

Gene:CD83; CD83 molecule
Aliases: BL11, HB15
Summary:The protein encoded by this gene is a single-pass type I membrane protein and member of the immunoglobulin superfamily of receptors. The encoded protein may be involved in the regulation of antigen presentation. A soluble form of this protein can bind to dendritic cells and inhibit their maturation. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2011]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:CD83 antigen
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Cultured Cells
  • Mutation
  • Case-Control Studies
  • Messenger RNA
  • Stomach Cancer
  • Chromosome 6
  • Genetic Predisposition
  • T-Lymphocytes, Cytotoxic
  • Acute Lymphocytic Leukaemia
  • Tumor Escape
  • CD Antigens
  • Young Adult
  • Transfection
  • Gene Expression Profiling
  • Cancer Gene Expression Regulation
  • Cervical Cancer
  • Immunoglobulins
  • Immunotherapy
  • Single Nucleotide Polymorphism
  • Dendritic Cells
  • Cell Proliferation
  • CD40 Antigens
  • Chronic Myelogenous Leukemia
  • Cancer Vaccines
  • Cell Differentiation
  • Cytotoxicity, Immunologic
  • Viral Proteins
  • Membrane Glycoproteins
  • Cytokines
  • Apoptosis
  • Uteroglobin
  • Adenocarcinoma
  • B7-1 Antigen
  • Phenotype
  • Flow Cytometry
  • T-Lymphocytes, Regulatory
  • Interleukin-12
  • S100 Proteins
  • Immunophenotyping
Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: CD83 (cancer-related)

Liu C, Zheng Y, Tang J, et al.
Stimulation of DC-CIK with PADI4 Protein Can Significantly Elevate the Therapeutic Efficiency in Esophageal Cancer.
J Immunol Res. 2019; 2019:6587570 [PubMed] Free Access to Full Article Related Publications
Background: PADI4 has extensive expression in many tumors. This study applied PADI4 as a tumor marker to stimulate DC- (dendritic cell-) CIK (cytokine-induced killer), an immunotherapy approach.
Methods: A PADI4 expression plasmid was transfected into EC-originating ECA-109 cells. PADI4 gene was also inserted into a prokaryotic expression vector to produce recombinant protein. Lysate from PADI4-overexpressing cells or the purified recombinant PADI4 protein was used to load DCs, and the cells were then coincubated with CIK cells. DC and CIK cell phenotypes were determined using flow cytometry. The proliferation and viability of CIK cells were analyzed using trypan blue staining. The cytotoxic effect of DC-CIK cells on cultured ECA-109 cells was determined using CCK8 assays. Tumor-bearing mice were prepared by injection of ECA-109 cells. DC-CIK cells stimulated with lysate from PADI4-overexpressing cells or the PADI4 recombinant protein were injected into the tumor-bearing mice. The tumor growth was measured with magnetic resonance imaging (MRI).
Results: Following incubation with lysate from PADI4-overexpressing cells, the ratio of CD40
Conclusion: This study demonstrates that stimulation of DC-CIK cells with PADI4 significantly suppressed tumor growth in tumor-bearing mice by promoting DC maturation, CIK cell proliferation, and cytotoxicity. PADI4 may be a potential tumor marker that could be used to improve the therapeutic efficiency of DC-CIK cells.

Lacher MD, Bauer G, Fury B, et al.
SV-BR-1-GM, a Clinically Effective GM-CSF-Secreting Breast Cancer Cell Line, Expresses an Immune Signature and Directly Activates CD4
Front Immunol. 2018; 9:776 [PubMed] Free Access to Full Article Related Publications
Targeted cancer immunotherapy with irradiated, granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting, allogeneic cancer cell lines has been an effective approach to reduce tumor burden in several patients. It is generally assumed that to be effective, these cell lines need to express immunogenic antigens coexpressed in patient tumor cells, and antigen-presenting cells need to take up such antigens then present them to patient T cells. We have previously reported that, in a phase I pilot study ( NCT00095862), a subject with stage IV breast cancer experienced substantial regression of breast, lung, and brain lesions following inoculation with clinical formulations of SV-BR-1-GM, a GM-CSF-secreting breast tumor cell line. To identify diagnostic features permitting the prospective identification of patients likely to benefit from SV-BR-1-GM, we conducted a molecular analysis of the SV-BR-1-GM cell line and of patient-derived blood, as well as a tumor specimen. Compared to normal human breast cells, SV-BR-1-GM cells overexpress genes encoding tumor-associated antigens (TAAs) such as PRAME, a cancer/testis antigen. Curiously, despite its presumptive breast epithelial origin, the cell line expresses major histocompatibility complex (MHC) class II genes (

Gulubova M, Aleksandrova E, Vlaykova T
Promoter polymorphisms in TGFB1 and IL10 genes influence tumor dendritic cells infiltration, development and prognosis of colorectal cancer.
J Gene Med. 2018; 20(2-3):e3005 [PubMed] Related Publications
BACKGROUND: Anti-inflammatory cytokines such as interleukin (IL)-10 and transforming growth factor (TGF)-β1 have a complex role in the development of colorectal cancer (CRC). Dendritic cells (DCs) are the cellular component of the inflammatory microenvironment in the tumor and infiltration of tumors by DCs is associated with better prognosis and fewer metastases.
METHODS: In the present study, we explored the role of two single nucleotide polymorphisms (SNPs) in the promoter regions of TGFB1 and IL10 genes and their associations with infiltrating DCs in CRC.A case-control study was designed. Genotyping was performed via the polymerase chain reaction-restriction fragment length polymorphism method and DC infiltration was determined immunohistochemically.
RESULTS: For the TGFΒ1 -509C/T SNP, we found that the T allele was less frequent in patients than in controls (p = 0.031) and the TT-genotype had a 2.74-fold lower risk for CRC than the CC-genotype (odds ratio = 0.365, 95% confidence interval = 0.15-0.88, p = 0.015). Additionally, the TT carriers had the shortest median survival (14.4 months) (p = 0.045). The C-allele genotypes had a significantly longer survival compared to TT carriers (p = 0.018). The CC genotype was associated with a lower cellular density of CD11c in the invasive margin of the tumor (p = 0.033), whereas there was an opposite finding for CD83+ DCs (p = 0.037). Carriers of A-allele genotypes of the IL10 -1080A/G SNP had significantly lower CD83+ cells (p = 0.046) in the tumor invasive margin.
CONCLUSIONS: The T-allele of the TGFB1 -509C/T SNP might be a protective factor for development of CRC, although, in the course of the disease, this variant allele might be associated with more unfavorable prognosis of the patients.

Jiang Q, Wang X, Qian M, et al.
Effects of epidermal growth factor receptor fusion protein on the cytotoxic activity of SOCS1-silenced dendritic cells in vitro.
Oncol Rep. 2018; 39(3):1306-1312 [PubMed] Related Publications
The aim of the present study was to observe the effects of cytokine signaling suppressor 1 (SOCS1)-silenced dendritic cells (DCs) pulsed with epidermal growth factor receptor (EGFR) fusion protein on the activation of T lymphocyte and cytotoxic T-lymphocyte (CTL) activity against Hep-2 cells. DCs were derived from the medullary cells of mice and authenticated by flow cytometry (FCM). Recombinant glutathione-S-transferase (GST)-EGFR fusion protein was produced and purified. After being pulsed with it, DCs were modified by recombinant SOCS1-siRNA adenoviral to silence SOCS1 gene expression. The maturation of DCs was evaluated by FCM. The effects of modified DCs on T-cell proliferation were assessed by MTT assay. The killing effects against Hep-2 cells of CTL were assessed by lactate dehydrogenase (LDH) release assay. High-purity DCs from the medullary cells of mice were obtained. Compared with the control, EGFR-pulsed DCs displayed higher expression of cell surface molecules, including CD83, CD860 and HLA-DR. The MTT assay revealed that all of the EGFR-pulsed, SOCS1‑silenced and EGFR-pulsed plus SOCS1-silenced DCs had an enhanced capacity to stimulate T-lymphocyte proliferation. As expected, EGFR-pulsed plus SOCS1-silenced DCs had the strongest effects on T-cell proliferation. The splenic T cells isolated from both EGFR-pulsed DC-immunized mice and EGFR-pulsed plus SOCS1-silenced DC-immunized mice enhanced the cytotoxicity against Hep-2 cells, while T cells from EGFR‑pulsed plus SOCS1-silenced DC-immunized mice exhibited significantly higher cytotoxicity than those from EGFR-DC-immunized mice. The EGFR-pulsed SOCS1‑siRNA-silenced DCs had the strongest effects on activation of T-cell proliferation and the CTL activity against Hep-2 cells.

De Almeida CV, Zamame JA, Romagnoli GG, et al.
Treatment of colon cancer cells with 5-fluorouracil can improve the effectiveness of RNA-transfected antitumor dendritic cell vaccine.
Oncol Rep. 2017; 38(1):561-568 [PubMed] Related Publications
Non-cytotoxic concentrations of selected chemotherapeutic agents amplify the antigen presentation capacity of dendritic cells (DCs) and are able to increase the immunogenicity of the colon cancer cell lineage HCT‑116, as previously demonstrated by our group. Since this functional alteration was associated with changes in gene expression, we aimed to evaluate whether transcriptional changes of tumor cells can be transferred to DCs, increasing their ability to induce a specific antitumor response. Therefore, HCT‑116 cells were treated with two different concentrations of 5-fluorouracil (5-FU), and their total RNA was transfected into human monocyte-derived DC, which function was evaluated through their ability to stimulate the proliferation of normal allogeneic T lymphocytes (MLR), and to generate cytolytic T cells. The transfected DCs demonstrated an increased percentage of CD83+, HLA-DR+, CD80+ and CD86+ cells. These phenotypical changes were followed by functional improvement demonstrated by the increased capacity of these DC to induce allogeneic T cell proliferation and to generate specific anti-HCT‑116 cytolytic T cells, as demonstrated by IFN-γ production following in vitro challenge with tumor cells. Our results allow us to conclude that treatment of tumor cells with a non-toxic concentration of 5-FU induces immunogenic changes that are transferred to DC by transfection of total RNA.

Zhou J, Ma P, Li J, et al.
Improvement of the cytotoxic T lymphocyte response against hepatocellular carcinoma by transduction of cancer cells with an adeno-associated virus carrying the interferon-γ gene.
Mol Med Rep. 2016; 13(4):3197-205 [PubMed] Related Publications
Dendritic cell (DC)-based antigen-targeted immunotherapy may offer effective adjuvant therapy for hepatocellular carcinoma (HCC), in which cytotoxic T lymphocytes (CTLs) are key. However, in a number of cases, the activity of CTLs is completely inhibited due to the downregulated expression of major human leukocyte antigen (HLA) class I molecules by HCC cells. The aim of the present study was to overcome this issue. Hep3B cells were transduced by HCC‑specific recombinant adeno‑associated virus (rAAV) carrying human α‑fetoprotein promoter (AFPp) and the interferon‑γ (IFN‑γ) gene (rAAV/AFPp‑IFN‑γ). rAAV carrying the cytomegalovirus promoter (CMVp) and human α‑fetoprotein (AFP) gene (rAAV/CMVp‑AFP) was used to transduce professional antigen‑presenting DCs for the purpose of stimulating a CTL response. It was observed that transduction of DCs with rAAV/CMVp‑AFP resulted in: (i) AFP and interleukin‑12 expression; (ii) high expression levels of cluster of differentiation (CD)80, CD83, CD86, CD40, HLA‑death receptor and CD1a; (iii) T cell populations with marked IFN‑γ expression; (iv) a high percentage of CD69+/CD8+ T cells; and (v) the activity of CTLs against HLA‑A2‑expressing Hep3B cells. The transduction of Hep3B cells with rAAV/AFPp‑IFN‑γ resulted in: (i) IFN‑γ expression; (ii) upregulated expression of HLA‑A2; and (iii) an improved CTL response against HLA‑A2‑deficient Hep3B cells. rAAV/CMVp‑AFP‑transduced DCs elicited an AFP‑specific and HLA‑class I‑restricted CTL response against Hep3B cells. In conclusion, it was shown that the transduction of Hep3B with rAAV/AFPp-IFN-γ upregulated the expression of HLA-A2 and improved the sensitivity to CTL response.

Bock S, Murgueitio MS, Wolber G, Weindl G
Acute myeloid leukaemia-derived Langerhans-like cells enhance Th1 polarization upon TLR2 engagement.
Pharmacol Res. 2016; 105:44-53 [PubMed] Related Publications
Langerhans cells (LCs) represent a highly specialized subset of epidermal dendritic cells (DCs), yet not fully understood in their function of balancing skin immunity. Here, we investigated in vitro generated Langerhans-like cells obtained from the human acute myeloid leukaemia cell line MUTZ-3 (MUTZ-LCs) to study TLR- and cytokine-dependent activation of epidermal DCs. MUTZ-LCs revealed high TLR2 expression and responded robustly to TLR2 engagement, confirmed by increased CD83, CD86, PD-L1 and IDO expression, upregulated IL-6, IL-12p40 and IL-23p19 mRNA levels IL-8 release. TLR2 activation reduced CCR6 and elevated CCR7 mRNA expression and induced migration of MUTZ-LCs towards CCL21. Similar results were obtained by stimulation with pro-inflammatory cytokines TNF-α and IL-1β whereas ligands of TLR3 and TLR4 failed to induce a fully mature phenotype. Despite limited cytokine gene expression and production for TLR2-activated MUTZ-LCs, co-culture with naive CD4(+) T cells led to significantly increased IFN-γ and IL-22 levels indicating Th1 differentiation independent of IL-12. TLR2-mediated effects were blocked by the putative TLR2/1 antagonist CU-CPT22, however, no selectivity for either TLR2/1 or TLR2/6 was observed. Computer-aided docking studies confirmed non-selective binding of the TLR2 antagonist. Taken together, our results indicate a critical role for TLR2 signalling in MUTZ-LCs considering the leukemic origin of the generated Langerhans-like cells.

Meng FD, Wang S, Jiang YH, Sui CG
Antitumor effect of dendritic cells transfected with prostate-specific membrane antigen recombinant adenovirus on prostate cancer: An in vitro study.
Mol Med Rep. 2016; 13(3):2124-34 [PubMed] Related Publications
The aim of the present study was to construct a dendritic cell (DC) vaccine transfected with a prostate-specific membrane antigen (PSMA) recombinant adenovirus and to observe the ability of the recombinant DCs in eliciting a PSMA-directed T‑cell response to prostate cancer (PCa) in vitro. Replication‑defective adenoviral vectors, were constructed using the Adxsi system. The virus titer was measured by TCID50 assay, and the expression of the PSMA gene was identified by polymerase chain reaction (PCR) generation of peripheral blood mononuclear cell (PBMC) derived DCs in vitro. In addition, a PE‑7AAD apoptosis and necrosis kit was applied to detect the survival of DCs at different MOI values to determine the optimal MOI. Morphological changes of DC were observed under a fluorescence microscope, expression of the PSMA protein was detected by western blotting 48 h after transfection, the expression of DC markers prior to and following transfection was detected by direct immunofluorescence, and the interleukin (IL)-12 concentration in the culture supernatant of the three groups was measured by ELISA. The antitumor effect of DC-stimulated cytotoxic T lymphocytes (CTLs) on different PCa cell lines was analyzed using a Cell Counting Kit‑8 assay. The optimal MOI value was determined to be 200. The PSMA protein was expressed in DCs, and the recombinant adenovirus did not impact the maturation and morphological changes of the DCs. The expression levels of the co-stimulatory molecules, CD80, CD83, CD86 and HLA‑DR, were significantly higher in the Ad‑PSMA‑DC group than in the other two groups (P<0.05). The concentration of IL‑12 in the supernatant of the Ad‑PSMA‑DC group (79.51±1.60 pg) was comparable with that of the Ad‑GFP‑DC group (not significantly different), and the two were significantly higher than the non‑transfection group (P<0.05). The optimal effector to target (E:T) ratio was determined to be 40:1. However, at the same E:T ratio, the cytotoxic activity of PSMA‑DC‑T against the LNCap cells was markedly stronger than its activity against the other target cells (DU145 and 22RV; P<0.05); furthermore, the the cytotoxic activity of PSMA-DC-T against the LNCap cells was significantly higher than the anti‑LNCap effect of DC‑T cells in other groups (P<0.05). In vitro experiments indicated that mature DCs transfected with Ad‑PSMA secreted high concentrations of IL‑12 and elicited potent antitumor immune responses targeting PSMA‑expressing cells by stimulating the cytotoxic activity of CTLs.

Wang Z, Deng Z, Dahmane N, et al.
Telomeric repeat-containing RNA (TERRA) constitutes a nucleoprotein component of extracellular inflammatory exosomes.
Proc Natl Acad Sci U S A. 2015; 112(46):E6293-300 [PubMed] Free Access to Full Article Related Publications
Telomeric repeat-containing RNA (TERRA) has been identified as a telomere-associated regulator of chromosome end protection. Here, we report that TERRA can also be found in extracellular fractions that stimulate innate immune signaling. We identified extracellular forms of TERRA in mouse tumor and embryonic brain tissue, as well as in human tissue culture cell lines using RNA in situ hybridization. RNA-seq analyses revealed TERRA to be among the most highly represented transcripts in extracellular fractions derived from both normal and cancer patient blood plasma. Cell-free TERRA (cfTERRA) could be isolated from the exosome fractions derived from human lymphoblastoid cell line (LCL) culture media. cfTERRA is a shorter form (∼200 nt) of cellular TERRA and copurifies with CD63- and CD83-positive exosome vesicles that could be visualized by cyro-electron microscopy. These fractions were also enriched for histone proteins that physically associate with TERRA in extracellular ChIP assays. Incubation of cfTERRA-containing exosomes with peripheral blood mononuclear cells stimulated transcription of several inflammatory cytokine genes, including TNFα, IL6, and C-X-C chemokine 10 (CXCL10) Exosomes engineered with elevated TERRA or liposomes with synthetic TERRA further stimulated inflammatory cytokines, suggesting that exosome-associated TERRA augments innate immune signaling. These findings imply a previously unidentified extrinsic function for TERRA and a mechanism of communication between telomeres and innate immune signals in tissue and tumor microenvironments.

Chen H, Li Y, Lin X, et al.
Functional disruption of human leukocyte antigen II in human embryonic stem cell.
Biol Res. 2015; 48:59 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Theoretically human embryonic stem cells (hESCs) have the capacity to self-renew and differentiate into all human cell types. Therefore, the greatest promise of hESCs-based therapy is to replace the damaged tissues of patients suffering from traumatic or degenerative diseases by the exact same type of cells derived from hESCs. Allograft immune rejection is one of the obstacles for hESCs-based clinical applications. Human leukocyte antigen (HLA) II leads to CD4(+) T cells-mediated allograft rejection. Hence, we focus on optimizing hESCs for clinic application through gene modification.
RESULTS: Transcription activator-like effector nucleases (TALENs) were used to target MHC class II transactivator (CIITA) in hESCs efficiently. CIITA (-/-) hESCs did not show any difference in the differentiation potential and self-renewal capacity. Dendritic cells (DCs) derived from CIITA (-/-) hESCs expressed CD83 and CD86 but without the constitutive HLA II. Fibroblasts derived from CIITA (-/-) hESCs were powerless in IFN-γ inducible expression of HLA II.
CONCLUSION: We generated HLA II defected hESCs via deleting CIITA, a master regulator of constitutive and IFN-γ inducible expression of HLA II genes. CIITA (-/-) hESCs can differentiate into tissue cells with non-HLA II expression. It's promising that CIITA (-/-) hESCs-derived cells could be used in cell therapy (e.g., T cells and DCs) and escape the attack of receptors' CD4(+) T cells, which are the main effector cells of cellular immunity in allograft.

Ding Y, Shen J, Zhang G, et al.
CD40 controls CXCR5-induced recruitment of myeloid-derived suppressor cells to gastric cancer.
Oncotarget. 2015; 6(36):38901-11 [PubMed] Free Access to Full Article Related Publications
To explore the mechanisms of MDSC trafficking and accumulation during tumor progression. In this study, we report significant CD40 upregulation in tumor-infiltrating MDSC when compared with splenic MDSC. Microarray analyses comparing CD40(high) and CD40l(ow) MDSC revealed 1872 differentially expressed genes, including CD83, CXCR5, BTLA, CXCL9, TLR1, FLT3, NOD2 and CXCL10. In vivo experiments comparing wild-type (WT) and CD40 knockout (KO) mice demonstrated that CD40 critically regulates CXCR5 expression. Consistently, the transwell analysis confirmed the essential role of CXCR5-CXCL13 crosstalk in the migration of CD40+ MDSC toward gastric cancer. Furthermore, more MDSC accumulated in the gastric cancers of WT mice when compared with KO mice, and the WT tumors mostly contained CD40+ cells. Functionally, tumors grew faster in WT than KO mice. In conclusion, we demonstrate that CD40 expression upregulates the chemokine receptor CXCR5 and promotes MDSC migration toward and accumulation within cancer. Therefore, this study provides preliminary evidence that CD40 may stimulate tumor growth by enabling immune evasion via MDSC recruitment and inhibition of T cell expansion.

Riley CH, Brimnes MK, Hansen M, et al.
Interferon-α induces marked alterations in circulating regulatory T cells, NK cell subsets, and dendritic cells in patients with JAK2V617F-positive essential thrombocythemia and polycythemia vera.
Eur J Haematol. 2016; 97(1):83-92 [PubMed] Related Publications
Long-term therapy with IFN-α2 is associated with sustained major molecular remissions in JAK2-positive ET and PV. The efficacy of IFN-α2 may be partly mediated by modulation of immune cells, which was investigated in twenty patients with ET (n = 6) and PV (n = 14). The frequency of CD4(+) CD25(+) Foxp3(+) T cells was significantly increased during IFN-α2 treatment in all patients (P < 0.0001). A significant expansion of the CD56(bright) NK cells (P = 0.0002) and a concomitant decrease in the frequency of CD56(dim) NK cells (P < 0.0001) were also detected. Myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) were studied in nine patients, and decreased frequencies of both cell types were observed during the course of treatment. On both mDCs and pDCs, HLA-ABC expression was upregulated (P = 0.003), but decreasing expression levels of HLA-DR was detected on mDCs. The expression of CD40 (P = 0.002), CD83 (P = 0.03), and CD86 (P = 0.01) increased, but was confined to pDCs. Furthermore, PD-L1 expression was reduced on mDC (P = 0.003) and increased on pDCs (P = 0.02). No significant correlations were found between the changes in immune cells and hematological or molecular responses achieved in our cohort of patients. So forth, it remains to be revealed whether the profound changes in circulating immune cells contribute to the beneficial effects of long-term IFN-α2 treatment in some patients.

Schneider MA, Granzow M, Warth A, et al.
Glycodelin: A New Biomarker with Immunomodulatory Functions in Non-Small Cell Lung Cancer.
Clin Cancer Res. 2015; 21(15):3529-40 [PubMed] Related Publications
PURPOSE: In recent years, immune therapeutic strategies against non-small cell lung cancer (NSCLC) based on tissue-derived biomarkers, for example PD1/PD-L1 (CD274), have evolved as novel and promising treatment options. However, the crosstalk between tumor and immune cells is poorly understood. Glycodelin (gene name PAEP), initially described in the context of pregnancy and trophoblastic implantation, is a secreted immunosuppressive glycoprotein with an as-of-yet largely unknown function in lung cancer.
EXPERIMENTAL DESIGN: In this study, we characterized the expression and role of glycodelin in NSCLC through mRNA and protein expression analyses, functional knockdown experiments, and correlations with clinicopathologic parameters.
RESULTS: Glycodelin mRNA expression was significantly elevated in tumors (n = 336) compared with matched normal tissue (P < 0.0001). Overall survival (OS) was significantly reduced in NSCLC with high glycodelin mRNA levels in women but not in men. Glycodelin was detected in the sera of patients, and the levels correlated with recurrence and metastatic disease. Knockdown of glycodelin with siRNAs in NSCLC cell lines resulted in significant upregulation of immune system modulatory factors such as PDL1, CXCL5, CXCL16, MICA/B, and CD83 as well as proliferation stimulators EDN1 and HBEGF. Furthermore, decreased migration of tumor cells was observed.
CONCLUSIONS: Altogether, the comprehensive characterization of glycodelin in NSCLC provides strong support for its use as a biomarker with immune modulatory function.

Turbica I, Gallais Y, Gueguen C, et al.
Ectosomes from neutrophil-like cells down-regulate nickel-induced dendritic cell maturation and promote Th2 polarization.
J Leukoc Biol. 2015; 97(4):737-49 [PubMed] Related Publications
DCs are the first immune cells to be exposed to allergens, including chemical sensitizers, such as nickel, a human TLR4 agonist that induces DC maturation. In ACD, DCs can interact with PMNs that are recruited and activated, leading, in particular, to ectosome release. The objective of this work was to characterize the effects of PMN-Ect on DC functions in an ACD context. We first developed a standardized protocol to produce, characterize, and quantify ectosomes by use of human PLB-985 cells, differentiated into mature PMN (PLB-Ect). We then studied the in vitro effects of these purified ectosomes on human moDC functions in response to NiSO4 and to LPS, another TLR4 agonist. Confocal fluorescence microscopy showed that PLB-Ect was internalized by moDCs and localized in the lysosomal compartment. We then showed that PLB-Ect down-regulated NiSO4-induced moDC maturation, as witnessed by decreased expression of CD40, CD80, CD83, CD86, PDL-1, and HLA-DR and by decreased levels of IL-1β, IL-6, TNF-α, and IL-12p40 mRNAs. These effects were related to p38MAPK and NF-κB down-regulation. However, no increase in pan-regulatory DC marker genes (GILZ, CATC, C1QA) was observed; rather, levels of effector DC markers (Mx1, NMES1) were increased. Finally, when these PLB-Ect + NiSO4-treated moDCs were cocultured with CD4(+) T cells, a Th2 cytokine profile seemed to be induced, as shown, in particular, by enhanced IL-13 production. Together, these results suggest that the PMN-Ect can modulate DC maturation in response to nickel, a common chemical sensitizer responsible for ADC.

Théate I, van Baren N, Pilotte L, et al.
Extensive profiling of the expression of the indoleamine 2,3-dioxygenase 1 protein in normal and tumoral human tissues.
Cancer Immunol Res. 2015; 3(2):161-72 [PubMed] Related Publications
Tryptophan catabolism by indoleamine 2,3-dioxygenase 1 (IDO1) plays a key role in tumoral resistance to immune rejection. In humans, constitutive expression of IDO1 has been observed in several tumor types. However, a comprehensive analysis of its expression in normal and tumor tissues is still required to anticipate the risks and potential benefits of IDO1 inhibitors. Using a newly validated monoclonal antibody to human IDO1, we performed an extensive immunohistochemical analysis of IDO1 expression in normal and tumor tissues. In normal tissues, IDO1 was expressed by endothelial cells in the placenta and lung and by epithelial cells in the female genital tract. In lymphoid tissues, IDO1 was expressed in mature dendritic cells with a phenotype (CD83(+), DC-LAMP(+), langerin(-), CD123(-), CD163(-)) distinct from plasmacytoid dendritic cells. Importantly, IDO1-expressing dendritic cells were not enriched in tumor-draining lymph nodes, in contrast with previously reported findings. IDO1-expressing cells were observed in a large fraction (505/866, 58%) of human tumors. They comprised tumor cells, endothelial cells, and stromal cells in proportions that varied depending on the tumor type. Tumors showing the highest proportions of IDO1-immunolabeled samples were carcinomas of the endometrium and cervix, followed by kidney, lung, and colon. This hierarchy of IDO1 expression was confirmed by gene expression data mined from The Cancer Genome Atlas database. Expression of IDO1 may be used to select tumors likely to benefit from targeted therapy with IDO1 inhibitors.

Yang YF, Xue SY, Lu ZZ, et al.
Antitumor effects of oncolytic adenovirus armed with PSA-IZ-CD40L fusion gene against prostate cancer.
Gene Ther. 2014; 21(8):723-31 [PubMed] Related Publications
Advanced prostate cancer (PC) still remains incurable. Novel immunogene therapy shows promise as treatment strategy that can target both localized and metastasized PC. In this study, we have developed a PC-specific oncolytic adenovirus (Ad-PL-PPT-E1A) armed with fusion gene of prostate-specific antigen and CD40 ligand, and aimed to evaluate its therapeutic effect in vitro and in vivo. After they were rescued in human embryonic kidney 293 cells, we confirmed that Ad-PL-PPT-E1A could mediate the expression of E1A efficiently and produce abundant progeny viruses in PC cells in vitro. Our data showed that Ad-PL-PPT-E1A induced apoptosis and resulted in specific oncolytic toxicity in PC cells, which was detected by Annexin-V staining and crystal violet, respectively. After stimulation with lysates, immune phenotypes and cytokines expression of human dendritic cells was detected by flow cytometry and real-time polymerase chain reaction, respectively. And, the results showed that the lysate of Ad-PL-PPT-E1A-infected LNCaP cells upregulated the expression of CD80, CD83, CD86 and mRNA level of interleukin-6 (IL-6), IL-12, IL-23 and tumor necrosis factor-α significantly. In established PC3M cell-xenografted mouse models, Ad-PL-PPT-E1A treatment improved the survival and suppressed the tumor growth obviously. In conclusion, Ad-PL-PPT-E1A exhibited enhanced antitumor activity is a promising approach for gene therapy of advanced PC.

Ngo MC, Ando J, Leen AM, et al.
Complementation of antigen-presenting cells to generate T lymphocytes with broad target specificity.
J Immunother. 2014; 37(4):193-203 [PubMed] Free Access to Full Article Related Publications
Antigen-specific T cells provide a therapy for cancer that is highly specific, self-replicating, and potentially devoid of toxicity. Ideally, tumor-specific T cells should recognize multiple epitopes on multiple antigens to prevent tumor immune escape. However the large-scale expansion of such broad-spectrum T cells has been limited by the availability of potent autologous antigen-presenting cells that can present antigens on the polymorphic array of each patient's HLA allotype. We evaluated a novel antigen-presenting complex (KATpx) in which antigens in the form of peptide libraries can be presented by autologous activated T cells, whereas costimulation is complemented in trans by an HLA-negative K562 cell line genetically modified to express CD80, CD83, CD86, and 4-1BBL (K562cs). The additional costimulation provided by K562cs significantly enhanced T-cell expansion in culture over autologous activated T cells alone while maintaining antigen specificity. We validated this antigen-presenting system by generating Epstein-Barr virus (EBV) antigen-specific T cells from healthy donors and from patients with EBV-positive malignancies including nasopharyngeal carcinoma and multiply relapsed EBV-positive lymphoma. These T cells were specific for EBNA1, LMP1, and LMP2, the viral antigens expressed in these type 2 latency EBV-associated malignancies. The KATpx system consistently activated and expanded antigen-specific T cells both from healthy donors and from 5 of 6 patients with lymphoma and 6 of 6 with nasopharyngeal carcinoma, while simplifying the process for generating APCs by eliminating the need for live virus (EBV) or viral vectors to force expression of transgenic EBV antigens. Hence, KATpx provides a robust, reliable, and scalable process to expand tumor-directed T cells for the treatment of virus-associated cancers.

Döring C, Hansmann ML, Agostinelli C, et al.
A novel immunohistochemical classifier to distinguish Hodgkin lymphoma from ALK anaplastic large cell lymphoma.
Mod Pathol. 2014; 27(10):1345-54 [PubMed] Related Publications
Classical Hodgkin lymphoma and ALK(-) anaplastic large cell lymphoma share many features like strong CD30 expression and usually loss of B- and T-cell markers. However, their clinical course is dramatically different with curability rates of >90% for classical Hodgkin lymphoma and an unfavorable prognosis for anaplastic large cell lymphoma. Classical Hodgkin lymphoma and ALK(-) anaplastic large cell lymphoma can usually be distinguished by PAX5 expression in the Hodgkin and Reed-Sternberg cells of classical Hodgkin lymphoma and expression of cytotoxic molecules in tumor cells of anaplastic large cell lymphoma. However, in some cases the differential diagnosis is difficult owing to absence of established markers. To be able to better classify these cases, we reevaluated gene expression data of microdissected tumor cells of both lymphomas for differentially expressed genes. A classifier was established, comprising four genes strongly expressed in Hodgkin and Reed-Sternberg cells of classical Hodgkin lymphoma (MDC/CCL22, CD83, STAT3, and TUBB2B). Applying this classifier to a test cohort, Hodgkin lymphoma was successfully distinguished from ALK(-) anaplastic large cell lymphoma with an accuracy of 97% (43/44). MDC/CCL22, CD83, and STAT3 have also been found to be expressed in antigen-presenting cells. Therefore, based on our established classifier, Hodgkin and Reed-Sternberg cells differ from tumor cells of anaplastic large cell lymphoma, which can successfully be applied for practical purposes in histopathologic diagnostics.

Ahmed Ali HA, Di J, Mei W, et al.
Antitumor activity of lentivirus-mediated interleukin -12 gene modified dendritic cells in human lung cancer in vitro.
Asian Pac J Cancer Prev. 2014; 15(2):611-6 [PubMed] Related Publications
OBJECTIVES: Dendritic cell (DC)-based tumor immunotherapy needs an immunogenic tumor associated antigen (TAA) and an effective approach for its presentation to lymphocytes. In this study we explored whether transduction of DCs with lentiviruses (LVs) expressing the human interleukin-12 gene could stimulate antigen- specific cytotoxic T cells (CTLs) against human lung cancer cells in vitro.
METHODS: Peripheral blood monocyte- derived DCs were transduced with a lentiviral vector encoding human IL-12 gene (LV-12). The anticipated target of the human IL-12 gene was detected by RT-PCR. The concentration of IL-12 in the culture supernatant of DCs was measured by ELISA.Transduction efficiencies and CD83 phenotypes of DCs were assessed by flow cytometry. DCs were pulsed with tumor antigen of lung cancer cells (DC+Ag) and transduced with LV-12 (DC-LV-12+Ag). Stimulation of T lymphocyte proliferation by DCs and activation of cytotoxic T-lymphocytes (CTL) stimulated by LV-12 transduced DCs pulsed with tumor antigen against A549 lung cancer cells were assessed with methyl thiazolyltetrazolium (MTT).
RESULTS: A recombinant lentivirus expressing the IL-12 gene was successfully constructed. DC transduced with LV-12 produced higher levels of IL-12 and expressed higher levels of CD83 than non-transduced. The DC modified by interleukin -12 gene and pulsed with tumor antigen demonstrated good stimulation of lymphocyte proliferation, induction of antigen-specific cytotoxic T lymphocytes and anti- tumor effects.
CONCLUSIONS: Dendritic cells transduced with a lentivirus-mediated interleukin-12 gene have an enhanced ability to kill lung cancer cells through promoting T lymphocyte proliferation and cytotoxicity.

Abdul Hafid SR, Chakravarthi S, Nesaretnam K, Radhakrishnan AK
Tocotrienol-adjuvanted dendritic cells inhibit tumor growth and metastasis: a murine model of breast cancer.
PLoS One. 2013; 8(9):e74753 [PubMed] Free Access to Full Article Related Publications
Tocotrienol-rich fraction (TRF) from palm oil is reported to possess anti-cancer and immune-enhancing effects. In this study, TRF supplementation was used as an adjuvant to enhance the anti-cancer effects of dendritic cells (DC)-based cancer vaccine in a syngeneic mouse model of breast cancer. Female BALB/c mice were inoculated with 4T1 cells in mammary pad to induce tumor. When the tumor was palpable, the mice in the experimental groups were injected subcutaneously with DC-pulsed with tumor lysate (TL) from 4T1 cells (DC+TL) once a week for three weeks and fed daily with 1 mg TRF or vehicle. Control mice received unpulsed DC and were fed with vehicle. The combined therapy of using DC+TL injections and TRF supplementation (DC+TL+TRF) inhibited (p<0.05) tumor growth and metastasis. Splenocytes from the DC+TL+TRF group cultured with mitomycin-C (MMC)-treated 4T1 cells produced higher (p<0.05) levels of IFN-γ and IL-12. The cytotoxic T-lymphocyte (CTL) assay also showed enhanced tumor-specific killing (p<0.05) by CD8(+) T-lymphocytes isolated from mice in the DC+TL+TRF group. This study shows that TRF has the potential to be used as an adjuvant to enhance effectiveness of DC-based vaccines.

Gulubova M, Manolova I, Ananiev J, et al.
Relationship of TGF-β1 and Smad7 expression with decreased dendritic cell infiltration in liver gastrointestinal cancer metastasis.
APMIS. 2013; 121(10):967-75 [PubMed] Related Publications
Immune responses and their modulation within the liver are critical to the outcome of liver malignancies. In late-stage tumors, secreted TGF-β promotes oncogenic functions and can confer tolerogenicity to some immune cells like DCs. The TGF-β signaling pathway is involved in the control of several biological processes, including immunosurveillance. The aim of the present study was to assess CD1a(+) and CD83(+) DCs and to evaluate the impact of TGF-β pathway on DCs maturation and distribution in the liver metastases from gastric and colorectal tumors. The percentage of CD83(+) DCs in the liver tissue, surrounding metastasis and in the metastasis-free liver was measured by flow cytometry, and TGF-β levels were assessed in the tissue supernatant from the peritumoral liver after mononuclear cell isolation and in the sera of the same patients. CD1a(+) and CD83(+) DCs were observed in the tumor stroma and border. Out of 73 patients, there was cytoplasmic reactivity: of TGF-β1 in 37 (50.7%); of Smad4 in 62 (84.9%); of Smad7 in 46 (63%), and of TGFβRII in 39 (53.4%) of the metastases. The TGF-β1 expression in tumor cell cytoplasm correlated with low CD1a(+) and low CD83(+) DCs infiltration. The tissue levels of TGF-β1, measured by ELISA in the supernatant were significantly increased in metastases than in normal liver. Using a two-color FACS analysis, we found that the percentage of HLA-DR(+) CD83(+) DCs in metastases was significantly decreased as compared with metastasis-free liver tissue. In conclusion, the positive and negative correlations between the mediators from the TGF-β pathway implied the existence of imbalance and suppression of this cytokine activity. The presence of increased TGF-β expression by immunohistochemistry in tumor cells was confirmed by detection of increased TGF-β tissue level in the supernatant from the tissue homogenate. The observation of low numbers of CD1a(+) and CD83(+) DCs in tumor stroma correlated with TGF-β overexpression in tumor cells, a fact that well documents the immunosuppressive role of TGF-β in metastasis development. The increased percentage of CD83(+) DCs in the peritumoral tissue supposes that there could be active recruitment or local differentiation of DCs in the metastasis border, but inside the tumor the immune cells recruitment and activity are suppressed by TGF-β and by other cytokines.

Wang Y, Deng B, Tang W, et al.
TGF-β1 secreted by hepatocellular carcinoma induces the expression of the Foxp3 gene and suppresses antitumor immunity in the tumor microenvironment.
Dig Dis Sci. 2013; 58(6):1644-52 [PubMed] Related Publications
AIM: The purpose of this study was to explore the mechanisms of TGF-β1 mediated immunosuppression in tumor stroma.
METHODS: The expression of TGF-β1 was investigated in Huh7, Hep 3B, SGC-7901, Eca-109 and Hepa1-6 cell lines using immunofluorescence. Knocked-down TGF-β1 of the Hepa1-6 cell line was established through lentivirus-based RNA interference. The interference efficiency of the TGF-β1 gene was tested by real-time PCR and ELISA; the expression of Foxp3, IFN-γ and CD83 in CD4(+), CD8(+) or dendritic cells was examined via flow cytometry; and the tumorigenic ability of the cancer cells was investigated in the animal experiments.
RESULTS: The diverse digestive cancer cells were found to secrete TGF-β1, mRNA of which was knocked down by 78 % thanks to lentivirus-based interference in Hepa1-6 cells. Flow cytometry showed that CD4(+)CD25(+)Foxp3(+) regulatory T cells significantly increased in hepatocellular carcinoma patients when compared with those in the healthy controls. The supernatant from Hepa1-6 cells and recombinant TGF-β1 significantly induced the expression of Foxp3 gene in vitro, while that from sh TGF-β1 Hepa1-6 cells restored it. Hepa1-6 cells inhibited IFN-γ and CD83 expression in CD8(+) or dendritic cells by secreting TGF-β1. The animal experiments indicated that the knockdown TGF-β1 gene impaired the tumorigenic ability of Hepa1-6 cells.
CONCLUSION: TGF-β1, expressed in cancer cells, might be a potential therapeutic target for cancer treatment.

Xue G, Cheng Y, Ran F, et al.
SLC gene-modified dendritic cells mediate T cell-dependent anti-gastric cancer immune responses in vitro.
Oncol Rep. 2013; 29(2):595-604 [PubMed] Related Publications
Dendritic cells (DCs) are potent professional antigen-presenting cells (APCs) with the ability to prime naïve T cells, and play an important role in the initiation and regulation of immune responses. In this study, we constructed a recombinant adenovirus carrying the SLC gene (Ad-SLC), and detected the biological effects of Ad-SLC-modified DCs as an adjuvant for the initiation of gastric cancer immune responses. Human DCs were transfected with Ad-SLC and the recombinant adenovirus carrying the β-galactosidase gene, Ad-LacZ, respectively. Modified DCs were pulsed with the cell lysate antigen of SGC-7901 cells (a type of gastric cancer cell line) and co-cultured with autologous T cells. The T cells were harvested and incubated with SGC-7901 cells and the cytotoxic function of the T cells was detected. Based on the data, the expression of mature DC phenotypes CD83 and CCR7 was upregulated after transfection with Ad-SLC and the chemotaxis function of DCs was augmented after transfection with Ad-SLC. Moreover, the expression of RANTES in DCs was upregulated by Ad-SLC transfection, while expression levels of IL-12p70 and IL-10 were not significantly altered. When co-cultured with autologous T cells, DCs modified with the SLC gene and pulsed with SGC-7901 cell lysates significantly promoted the proliferation of autologous T cells and induced Th1 differentiation, and displayed a strong cytotoxicity to SGC-7901 cells. In conclusion, Ad-SLC promoted DC maturation, enhancing the ability of DCs for T-cell chemotaxis and T-cell stimulation, and induced specific anti-gastric cancer cellular immunity. Recombinant Ad-SLC-modified DCs may be used as an adjuvant to induce an effective anti-gastric cancer immune response.

Victora GD, Dominguez-Sola D, Holmes AB, et al.
Identification of human germinal center light and dark zone cells and their relationship to human B-cell lymphomas.
Blood. 2012; 120(11):2240-8 [PubMed] Free Access to Full Article Related Publications
Germinal centers (GCs) are sites of B-cell clonal expansion, hypermutation, and selection. GCs are polarized into dark (DZ) and light zones (LZ), a distinction that is of key importance to GC selection. However, the difference between the B cells in each of these zones in humans remains unclear. We show that, as in mice, CXCR4 and CD83 can be used to distinguish human LZ and DZ cells. Using these markers, we show that LZ and DZ cells in mice and humans differ only in the expression of characteristic "activation" and "proliferation" programs, suggesting that these populations represent alternating states of a single-cell type rather than distinct differentiation stages. In addition, LZ/DZ transcriptional profiling shows that, with the exception of "molecular" Burkitt lymphomas, nearly all human B-cell malignancies closely resemble LZ cells, which has important implications for our understanding of the molecular programs of lymphomagenesis.

Tittarelli A, González FE, Pereda C, et al.
Toll-like receptor 4 gene polymorphism influences dendritic cell in vitro function and clinical outcomes in vaccinated melanoma patients.
Cancer Immunol Immunother. 2012; 61(11):2067-77 [PubMed] Related Publications
Toll-like receptor 4 (TLR4) is expressed on dendritic cells (DCs), sensing environmental danger molecules that induce their activation and maturation. Recently, we reported a method for the production of therapeutic DCs against melanoma, called tumor antigen-presenting cells (TAPCells), using a heat-shocked allogeneic melanoma cell lysate (TRIMEL) as an activation factor and antigen provider. Since TRIMEL contains endogenous TLR4 ligands, we evaluated the role of TLR4 in TAPCells differentiation by antibody neutralization and the association of a Tlr4 polymorphism (896A/G) (Asp299Gly), determined by PCR-RFLP, with the in vitro activation capacity and the clinical outcome of TAPCells-vaccinated patients. Antibody blocking of monocyte TLR4 inhibited surface expression, determined by flow cytometry, of the major histocompatibility complex class I, CCR7, CD80, CD83 and CD86 on TAPCells, reduced interleukin (IL)-6 and tumor necrosis factor -α gene expression evaluated by qRT-PCR, and also inhibited the TAPCells-mediated interferon-γ (IFN-γ) secretion of melanoma-specific CD8(+) T cells determined by ELISpot (p < 0.01). Moreover, CD8(+) T-cell activation capacity was significantly reduced in TAPCells bearing the TLR4 Asp299Gly receptor (p < 0.05). Finally, TAPCells-vaccinated stage-IV melanoma patients bearing the Tlr4 896G allele showed a shortened post-therapy median survival rate compared with those carrying the Tlr4 896A allele (p < 0.05; log-rank test). Our results indicate that TLR4 is a key receptor for the tumor lysate-mediated in vitro generation of clinically efficient antigen-presenting cells. Further analysis of patients included in different vaccine protocols is necessary for definitively establishing a role for TLR4 polymorphism in clinical responses.

Liang W, Wang XF
In vitro induction of specific anti-tumoral immunity against laryngeal carcinoma by using human interleukin-12 gene-transfected dendritic cells.
Chin Med J (Engl). 2011; 124(9):1357-61 [PubMed] Related Publications
BACKGROUND: Objective evaluation of the antitumor effect of interleukin-12 (IL-12) gene-transfected dendritic cell (DC) vaccine on laryngeal carcinoma requires in vivo and in vitro tests. The aim of this study was to investigate the function of IL-12 gene transfected DC at initiating specific immune response to laryngeal carcinoma in vitro.
METHODS: Recombinant adenovirus with IL-12 gene was constructed. DCs were isolated from the peripheral blood of patients with laryngeal carcinoma, pulsed with tumor lysate of laryngeal carcinoma cells (DC⁺Ag), and transfected with IL-12 (DC-IL-12⁺Ag). The cells pheotypes including CD83, CD86 and HLA-DR on surface of DCs were assayed by flow cytometry (FCM). The concentration of IL-12 in culture supernatant of DCs and interferon γ (IFN-γ) in culture supernatant of T cells cocultured with DCs were quantified by ELISA. Methyl thiazolys tetrazolium (MTT) was used to evaluate proliferation of autologous T lymphocytes and activation of cytotoxic T lymphocytes (CTL) stimulated by IL-12-transfected DCs pulsed with tumor lysate against laryngeal carcinoma cells.
RESULTS: The recombinant adenovirus expressing IL-12 gene was constructed successfully. Gene-transfected DC plused with tumor lysate with IL-12 (DC-IL-12⁺Ag) expressed higher level of CD83, CD86 and produced higher level of IL-12 than untransfected DCs (DC⁺Ag) (CD83: (60.2 ± 1.8)% vs. (50.7 ± 1.2)%, P < 0.05; CD86: (88.9 ± 2.1)% vs. (78.2 ± 3.9)%, P < 0.05; IL-12: (262.5 ± 3.0) ng/L vs. (103.8 ± 5.1) ng/L, P < 0.05). The proliferation of autologous T lymphocytes and production of IFN-γ stimulated by DC transfected with IL-12 were more obviously than untransfected DCs. Cytotoxicity of CTL stimulated by IL-12-transfected DC pulsed with tumor lysate against laryngeal carcinoma cells were significantly stronger than stimulated by untransfected DC.
CONCLUSION: It is a promising approach for IL-12-transfected DC pulsed with tumor lysate to increase the antitumoral effect.

Cornforth AN, Fowler AW, Carbonell DJ, et al.
Characterization of interferon-γ-treated melanoma tumor cells for use in dendritic cell-based immunotherapy.
Cancer Biother Radiopharm. 2011; 26(3):345-51 [PubMed] Related Publications
Efficient delivery of tumor-associated antigens to professional antigen-presenting cells is important for inducing a response in patients receiving cancer immunotherapy. Interferon-gamma (IFN-γ) is used by the immune system to combat viral and fungal infections by restricting cell proliferation and, in some cases, inducing apoptosis. Using IFN-γ to activate target tumor cells prior to antigen loading of dendritic cells (DCs) may enhance the beneficial qualities of whole-cell tumor vaccines. The incubation of melanoma cell cultures with IFN-γ resulted in an increase in the expression of major histocompatibility complex molecules and ICAM-1 but generally decreased the expression of melanoma-associated tumor antigens. Additionally, important immune-stimulating molecules (heat-shock proteins, high-mobility group box-1 protein, and calreticulin) were also present but differentially regulated by IFN-γ. Loading of DCs with IFN-γ-treated tumor cells resulted in a small but significant increase in the expression of CD83-positive DCs, indicating the initiation of DC maturation (p=0.019). IFN-γ treatment of melanoma cell lines prior to antigen loading of DCs may aid in antigen processing and presentation.

Tanaka M, Butler MO, Ansén S, et al.
Induction of HLA-DP4-restricted anti-survivin Th1 and Th2 responses using an artificial antigen-presenting cell.
Clin Cancer Res. 2011; 17(16):5392-401 [PubMed] Free Access to Full Article Related Publications
PURPOSE: In previous cancer vaccine clinical trials targeting survivin, induction of specific CD8(+) T-cell responses did not consistently lead to clinical responses. Considering the critical role of CD4(+) T-cell help in generating antitumor immunity, integration of anti-survivin CD4(+) T-cell responses may enhance the efficacy of anti-survivin cancer immunotherapy. Human leukocyte antigen (HLA)-DP4 is emerging as an attractive MHC target allele of CD4(+) T cell-mediated immunotherapy, because it is one of the most frequent HLA alleles in many ethnic groups. In this article, we aimed to elucidate DP4-restricted CD4(+) T-cell responses against survivin in cancer patients.
EXPERIMENTAL DESIGN: We generated a human cell-based artificial antigen-presenting cell (aAPC) expressing HLA-DP4, CD80, and CD83 and induced DP4-restricted antigen-specific CD4(+) T cells. The number, phenotype, effector function, and in vitro longevity of generated CD4(+) T cells were determined.
RESULTS: We first determined previously unknown DP4-restricted CD4(+) T-cell epitopes derived from cytomegalovirus pp65, to which sustained Th1-biased recall responses were induced in vitro by using DP4-aAPC. In contrast, DP4-aAPC induced in vitro both Th1 and Th2 long-lived anti-survivin CD4(+) T cells from cancer patients. Both survivin-specific Th1 and Th2 cells were able to recognize survivin-expressing tumors in a DP4-restricted manner. Neither survivin-specific interleukin 10 secreting Tr1 cells nor Th17 cells were induced by DP4-aAPC.
CONCLUSIONS: DP4-restricted anti-survivin Th1 and Th2 immunity with sufficient functional avidity can be induced from cancer patients. The development of strategies to concurrently induce both CD4(+) and CD8(+) T-cell responses against survivin is warranted for optimal anti-survivin cancer immunotherapy.

Fujimura T, Yamasaki K, Hidaka T, et al.
A synthetic NOD2 agonist, muramyl dipeptide (MDP)-Lys (L18) and IFN-β synergistically induce dendritic cell maturation with augmented IL-12 production and suppress melanoma growth.
J Dermatol Sci. 2011; 62(2):107-15 [PubMed] Related Publications
BACKGROUND: A synthetic NOD2 agonist, muramyl dipeptide (MDP)-Lys (L18), mimics the bacterial peptidoglycan moiety and acts as a powerful adjuvant that induces cell-mediated immunity.
OBJECTIVE: To investigate the induction of antitumor immune response for malignant melanoma by IFN-β in combination with MDP-Lys (L18) (IFN-MDP-Lys (L18)).
METHODS: Human monocyte-derived DCs (MoDCs) are stimulated with IFN-MDP-Lys (L18) in vitro. We assess the expression of costimulatory molecules on MoDCs by FACS. Moreover, we investigate the induction of Th1 cytokines by real time PCR and ELISA. Further to confirm the anti tumor immune response of IFN-MDP-Lys (L18) therapy, we examine the growth of B16F10 melanoma in vivo.
RESULTS: The stimulation of human MoDCs with IFN-MDP-Lys (L18) significantly augmented the production of IL-12p70, TNF-α, and IL-6 compared to that with MDP or that with IFN-β alone. IFN-MDP-Lys (L18) increased the expression of IL-12p35, IL-12p40, IL-10, TNF-α, IL-6 and IL-1β mRNA by MoDC using real-time PCR. The expression of CD83 and costimulatory molecules CD40, CD80, and CD86 was also augmented in MoDC treated with IFN-MDP-Lys (L18), which resulted in their augmented allogeneic T cell stimulation. In vivo, the administration of IFN-MDP-Lys (L18) significantly suppressed the growth of B16F10 melanoma, while the monotherapy of IFN-β or MDP-Lys (L18) did not significantly affect the tumor growth.
CONCLUSION: These findings suggest that IFN-MDP-Lys (L18) can be a promising adjuvant therapy for malignant melanoma.

Roy S, Goswami S, Bose A, et al.
Neem leaf glycoprotein partially rectifies suppressed dendritic cell functions and associated T cell efficacy in patients with stage IIIB cervical cancer.
Clin Vaccine Immunol. 2011; 18(4):571-9 [PubMed] Free Access to Full Article Related Publications
Myeloid-derived dendritic cells (DCs) generated from monocytes obtained from stage IIIB cervical cancer (CaCx IIIB) patients show dysfunctional maturation; thus, antitumor T cell functions are dysregulated. In an objective to optimize these dysregulated immune functions, the present study is focused on the ability of neem leaf glycoprotein (NLGP), a nontoxic preparation of the neem leaf, to induce optimum maturation of dendritic cells from CaCx IIIB patients. In vitro NLGP treatment of immature DCs (iDCs) obtained from CaCx IIIB patients results in upregulated expression of various cell surface markers (CD40, CD83, CD80, CD86, and HLA-ABC), which indicates DC maturation. Consequently, NLGP-matured DCs displayed balanced cytokine secretions, with type 1 bias and noteworthy functional properties. These DCs displayed substantial T cell allostimulatory capacity and promoted the generation of cytotoxic T lymphocytes (CTLs). Although NLGP-matured DCs derived from CaCx monocytes are generally subdued compared to those with a healthy monocyte origin, considerable revival of the suppressed DC-based immune functions is noted in vitro at a fairly advanced stage of CaCx, and thus, further exploration of ex vivo and in vivo DC-based vaccines is proposed. Moreover, the DC maturating efficacy of NLGP might be much more effective in the earlier stages of CaCx, where the extent of immune dysregulation is less and, thus, the scope of further investigation may be explored.

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